Aqueous Supramolecular Binder for High-Performance Lithium-Sulfur Batteries.

Developing an advanced electrode structure is highly important for obtaining lithium sulfur (Li-S) batteries with long life, low cost, and environmental friendliness. Some bottlenecks, such as large volume deformation and environmental pollution caused by the electrode preparation process, are still hindering the practical application of Li-S batteries. In this work, a new water-soluble, green, and environmentally friendly supramolecular binder (HUG) is successfully synthesized by modifying natural biopolymer (guar gum, GG) with HDI-UPy (cyanate containing pyrimidine groups). HUG can effectively resist electrode bulk deformation through a the unique three-dimensional nanonet-structure formed via covalent bonds and multiple hydrogen bonds. In addition, abundant polar groups of HUG have good adsorption properties for polysulfide and can inhibit the shuttle movement of polysulfide ions. Therefore, Li-S cell with HUG exhibits a high reversible capacity of 640 mAh g-1 after 200 cycles at 1C with a Coulombic efficiency of 99%.

Artesunate alleviates intracerebral haemorrhage secondary injury by inducing ferroptosis in M1-polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway.

Intracerebral haemorrhage (ICH) is a catastrophic subtype of stroke with severe morbidity and mortality. However, little progress has been made in the subsequent secondary injury. Artesunate, a water-soluble semi-synthetic derivative of artemisinin, exhibits remarkable pharmacological effects on anti-neuroinflammation. However, the effects of artesunate on ICH remain unknown. In the present study, haemoglobin (Hb) treatment in BV2 cell and collagenase type IV intracerebroventricular injection in Sprague-Dawley rats were used to establish in vitro and in vivo ICH models, respectively. For in vivo, the neurological scores, haematoma volume, brain oedema, inflammatory factors and iron deposition were evaluated. Besides, lipopolysaccharide (LPS) was used in in vitro to polarize BV2 cell to M1 phenotype. Cell viability, cellular reactive oxygen species (ROS), Fe2+ concentration, and lipid peroxidation levels, ferroptosis-associated proteins and mRNA, morphological of mitochondria were measured in vitro. Additionally, the AMP-activated protein kinase (AMPK)/mammalian/mechanistic target of rapamycin (mTOR) pathway were measured by western blot and immunofluorescence staining. The present in vivo results indicated that artesunate significantly ameliorated neurological deficits, haematoma volume and brain oedema in ICH rats. Besides, artesunate suppressed the M1-microglia relative inflammatory factors and up-regulated iron deposition. For in vitro, artesunate significantly selectively decreased the viability of LPS-stimulated BV2 cell. Furthermore, ROS and lipid peroxidation levels were up-regulated. And the glutathione peroxidase 4 (GPX4) were silenced via the AMPK/mTORC1 axis. Our finding supports that artesunate ameliorates the ICH secondary injury both in vitro and in vivo by inducing ferroptosis in microglia and further inhibiting inflammation mainly through the AMPK/mTORC1/GPX4 pathway. This finding may provide a novel target for ICH treatment.

Inhibition of PD-1 Alters the SHP1/2-PI3K/Akt Axis to Decrease M1 Polarization of Alveolar Macrophages in Lung Ischemia-Reperfusion Injury.

Polarization of alveolar macrophages (AMs) into the M1 phenotype contributes to inflammatory responses and tissue damage that occur during lung ischemia-reperfusion injury (LIRI). Programmed cell death factor-1 (PD-1) regulates polarization of macrophages, but its role in LIRI is unknown. We examined the role of PD-1 in AM polarization in models of LIRI in vivo and in vitro. Adult Sprague-Dawley rats were subjected to ischemia-reperfusion with or without pretreatment with a PD-1 inhibitor, SHP1/2 inhibitor, or Akt activator. Lung tissue damage and infiltration by M1-type AMs were assessed. As an in vitro complement to the animal studies, rat alveolar macrophages in culture were subjected to oxygen/glucose deprivation and reoxygenation. Levels of SHP1/2 and Akt proteins were evaluated using Western blots, while levels of pro-inflammatory cytokines were measured using enzyme-linked immunosorbent assays. Injury upregulated PD-1 both in vivo and in vitro. Inhibiting PD-1 reduced the number of M1-type AMs, expression of SHP1 and SHP2, and levels of inflammatory cytokines. At the same time, it partially restored Akt activation. Similar results were observed after inhibition of SHP1/2 or activation of the PI3K/Akt pathway. PD-1 promotes polarization of AMs to the M1 phenotype and inflammatory responses through the SHP1/2-PI3K/Akt axis. Inhibiting PD-1 may be an effective therapeutic strategy to limit LIRI.

Propofol produces neurotoxicity by inducing mitochondrial apoptosis.

Propofol is a fast and short-acting intravenous anesthetic widely used in clinical anesthesia and intensive care unit sedation. However, its use can cause abnormal effects on the central nervous system. Thus, the purpose of this study was to investigate the mechanism of propofol on primary hippocampal neuron injury. In addition, we aimed to determine whether a correlation exists between propofol and mitochondrial apoptosis-induced neurotoxicity. Hippocampal neurons cultured for 4 days were exposed to different drugs. The treatment groups were divided according to drug exposure into propofol, a rotenone inhibitor, and a coenzyme Q10 agonist groups. The final concentrations of propofol were 1, 10 and 100 µM. The content of ATP and reactive oxygen species (ROS) in the neurons of each group were detected using commercial kits in the culture supernatant after 3 h of drug exposure. Western blotting was used to analyze the expression of apoptosis-related proteins. The JC-1 kit was used to detect the mitochondrial membrane potential. The results revealed that, compared with the non-propofol treatment groups, the expression of apoptosis-related proteins, ATP content, and mitochondrial membrane potential were significantly decreased while the ROS content was markedly increased in the propofol treatment group. In conclusion, propofol treatment promoted damage to hippocampal neuronal mitochondria in a dose-dependent manner. This damage may lead to neuronal apoptosis and neurotoxicity by inducing the inhibition of mitochondrial respiratory chain complex I.

Identification of vasospasm biomarkers for cerebral hemorrhage via bio-informatics analysis.

BACKGROUND: The incidence of cerebral hemorrhage has rapidly increased over time, and vascular dysfunction has a significant influence on the pathogenesis and outcome of these patients. This is also the case for vasospasm in cerebral hemorrhage, but there is no method to assess this. We conducted this study to find molecular biomarkers of vasospasm in cerebral hemorrhage patients. METHODS: Raw data of GSE37924 was downloaded from the Gene Expression Omnibus (GEO) database, including 66 samples with cerebral vasospasm and 62 samples without cerebral vasospasm. Differentially expressed genes (DEGs) between samples with cerebral vasospasm and those without cerebral vasospasm were analyzed using the limma package in R software. To determine the functions of DEGs, we conducted functional enrichment analysis of DEGs through the clusterProfiler package in R. The protein-protein interaction (PPI) network of DEGs was constructed through STRING (https://string-db.org/) and generated via Cytoscape software. To understand the correlation between DEGs and immune-related genes, immune-related cerebral vasospasm genes were obtained via intersecting immune-related genes and cerebral vasospasm DEGs. We also compared the infiltration of 28 immune cells between cases with cerebral vasospasm and those without cerebral vasospasm. Finally, we constructed a model to perform the validation experiments. RESULTS: Of the DEGs, there were 24 upregulated and 21 downregulated genes in the vasospasm samples compared to the no-vasospasm samples. Functional enrichment analysis showed that these genes play key roles in several biological processes and signaling pathways such as the bone morphogenetic protein (BMP) signaling pathway, cellular response to BMP stimulus, natural killer cell chemotaxis, negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway, MHC protein complex binding, and receptor ligand activity, among others. CCL4, HLA-DQA1, IGF2, NTS, and so on were the significant immune-related genes. Furthermore, the immune cell infiltration results showed that there were differences between patients with vasospasm and those without vasospasm. Finally, we found that CCL4 had significantly higher expression in patients with vasospasm than those without vasospasm. CONCLUSIONS: CCL4 is an important regulator of vascular dysfunction in cerebral hemorrhage.

MYORG Mutation Heterozygosity Is Associated With Brain Calcification.

BACKGROUND: Biallelic mutations in the MYORG gene were first identified as the cause of recessively inherited primary familial brain calcification. Interestingly, some heterozygous carriers also exhibited brain calcifications. OBJECTIVES: To further investigate the role of single heterozygous MYORG mutations in the development of brain calcifications. METHODS: A nation-wide cohort of Chinese primary familial brain calcification probands was enrolled from March 2016 through September 2019. Mutational analysis of MYORG was performed in 435 primary familial brain calcification probands who were negative for mutations in the other four known primary familial brain calcification-causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1). RESULTS: Biallelic MYORG mutations were identified in 14 primary familial brain calcification patients from 10 unrelated families. Interestingly, 12 heterozygous carriers from seven of these families also exhibited mild-to-moderate brain calcifications. Moreover, single heterozygous mutations were detected in an additional 9 probands and in 7 of their family members affected with brain calcifications. In our cohort, clinical and imaging penetrance of individuals with biallelic mutations were 100%, whereas among individuals with heterozygous mutations, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 carriers had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG mutations, individuals with heterozygous mutations had brain calcifications with much lower calcification scores (P < 2e-16). CONCLUSIONS: Presence of brain calcifications in individuals with heterozygous MYORG mutations suggested a semidominant inheritance pattern with incomplete penetrance. This finding further expanded the genotype-phenotype correlations of MYORG-related primary familial brain calcification. © 2020 International Parkinson and Movement Disorder Society.

Dexmedetomidine attenuates the neurotoxicity of propofol toward primary hippocampal neurons in vitro via Erk1/2/CREB/BDNF signaling pathways.

BACKGROUND: Propofol is a commonly used general anesthetic for the induction and maintenance of anesthesia and critical care sedation in children, which may add risk to poor neurodevelopmental outcome. We aimed to evaluate the effect of propofol toward primary hippocampal neurons in vitro and the possibly neuroprotective effect of dexmedetomidine pretreatment, as well as the underlying mechanism. MATERIALS AND PROCEDURES: Primary hippocampal neurons were cultured for 8 days in vitro and pretreated with or without dexmedetomidine or phosphorylation inhibitors prior to propofol exposure. Cell viability was measured using cell counting kit-8 assays. Cell apoptosis was evaluated using a transmission electron microscope and flow cytometry analyses. Levels of mRNAs encoding signaling pathway intermediates were assessed using qRT-PCR. The expression of signaling pathway intermediates and apoptosis-related proteins was determined by Western blotting. RESULTS: Propofol significantly reduced cell viability, induced neuronal apoptosis, and downregulated the expression of the BDNF mRNA and the levels of the phospho-Erk1/2 (p-Erk1/2), phospho-CREB (p-CREB), and BDNF proteins. The dexmedetomidine pretreatment increased neuronal viability and alleviated propofol-induced neuronal apoptosis and rescued the propofol-induced downregulation of both the BDNF mRNA and the levels of the p-Erk1/2, p-CREB, and BDNF proteins. However, this neuroprotective effect was abolished by PD98059, H89, and KG501, further preventing the dexmedetomidine pretreatment from rescuing the propofol-induced downregulation of the BDNF mRNA and p-Erk1/2, p-CREB, and BDNF proteins. CONCLUSION: Dexmedetomidine alleviates propofol-induced cytotoxicity toward primary hippocampal neurons in vitro, which correlated with the activation of Erk1/2/CREB/BDNF signaling pathways.

Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway.

BACKGROUND: Propofol induces short- and long-term neurotoxicity. Our previous study showed that dexmedetomidine (Dex) can attenuate the propofol-induced acute neurotoxicity in rodents by enhancing the PI3K/Akt signaling. However, whether treatment of young rats with Dex could protect them from long-term neurotoxicity induced by propofol is unclear. MATERIALS AND METHODS: Seven-day-old male Sprague Dawley rats were randomized and injected intraperitoneally with saline (100 µL, NS), propofol (100 mg/kg), Dex (75 µg/kg), propofol (100 mg/kg) plus Dex (25, 50 or 75 µg/kg), 10% dimethyl sulfoxide (DMSO, 100 µL) or TDZD-8 (a GSK3ß inhibitor, 1 mg/kg), or intracerebroventricularly with DMSO (5 µL) or LY294002 (a PI3K inhibitor, 25 µg/5 µL DMSO). Other rats in the experimental group were injected with the same doses of propofol, Dex and LY294002 or TDZD-8. All the rats were monitored until they were 9 weeks old. Their spatial learning and memory were tested by Morris water maze. The neuronal apoptosis, expression of PSD95, expression and phosphorylation of Akt and GSK3ß and synaptic ultrastructures were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, immunohistochemistry, Western blot and transmission electron microscopy assays, respectively. RESULTS: Compared with the NS control group, young rats injected with intralipid, Dex, TDZD-8, LY294002 or DMSO alone did not show any significant change as they aged. Propofol significantly increased the escape latency time, hippocampal neuroapoptosis and synaptic ultrastructural changes but decreased the relative levels of PSD95 expression, and Akt and GSK3ß phosphorylation in the developing hippocampus of the rats. The neuronal toxic effects of propofol were significantly mitigated by the pretreatment with a higher dose of Dex. The neuroprotective effect of Dex was enhanced by the treatment with TDZD-8, but was completely abrogated by the treatment with LY294002. CONCLUSION: Our results indicated that the pretreatment of young rats with Dex attenuated the propofol-induced long-term neurotoxicity in their developing hippocampus by enhancing the PI3K/Akt signaling.

Hypoxic preconditioning reduces propofol-induced neuroapoptosis via regulation of Bcl-2 and Bax and downregulation of activated caspase-3 in the hippocampus of neonatal rats.

OBJECTIVE:  Evidence has shown that propofol may cause widespread apoptotic neurodegeneration. Hypoxic preconditioning (HPC) was previously demonstrated to provide neuroprotection and brain recovery from either acute or chronic neurodegeneration in several cellular and animal models. Therefore, the present study was designed to investigate the protective effects of hypoxic preconditioning on apoptosis caused by propofol in neonatal rats. METHODS: Propofol (100 mg/kg) was given to 7-day-old (P7) Sprague Dawley pups. Before the propofol injection, hypoxic preconditioning was administered by subjecting rats to five cycles of 10 min of hypoxia (8% O2) and 10 min of normoxia (21% O2), then 2 h of room air. We detected neuronal structure changes and apoptosis by hematoxylin and eosin (HE) staining and TUNEL assay, respectively. Bcl-2, Bax and cleaved-caspase-3 levels were quantified using Western blotting and immunohistochemistry. RESULT:  After treatment with propofol, Bcl-2 levels decreased and Bax and cleaved-caspase-3 levels increased. However, our results suggest that hypoxic preconditioning could reverse this change. Conclusion: Our results indicate that pretreatment with hypoxic preconditioning prevents propofol-induced neuroapoptosis by increasing the levels of Bcl-2 and decreasing the levels of Bax and cleaved-caspase-3.

Effect of fluoxetine on three-year recurrence in acute ischemic stroke: A randomized controlled clinical study.

OBJECTIVE: To evaluate the effect of fluoxetine on three-year recurrence rate of acute ischemic stroke. PATIENTS AND METHODS: 404 enrolled patients with acute ischemic stroke were randomly divided into control and treatment groups, and underwent conventional secondary preventive therapy for ischemic stroke. In addition, the treatment group was administered fluoxetine (20 mg daily for 90 days). A three-year follow-up was performed, and indicators related to risk factors of stroke were assessed at day 90 of follow-up. The effect of fluoxetine on the three-year recurrence rate of acute ischemic stroke was evaluated by survival analysis, as well as multifactor Cox regression analysis. RESULTS: The values of systolic blood pressure, blood total cholesterol, blood low density lipoprotein and glycosylated hemoglobin at day 90 of follow-up were significantly lower in treatment group than control group (P = 0.002, P = 0.002, P = 0.018, P = 0.011, respectively). The occurrence rates of epilepsy, gastrointestinal bleeding, syncope, allergic reactions, hemorrhagic infarction, and death were not significantly different between the two groups during the follow-up (P > 0.05). The recurrence-free survival rate of ischemic stroke was significantly lower in the treatment group than control group as assessed by the Kaplan-Meier test (85.1% Vs 75.7%, P = 0.016), as well as the recurrence-free survival rate after day 90 in the three-year follow-up (87.0% Vs 79.3%, P = 0.043). Multifactor Cox regression analysis demonstrated treatment with fluoxetine was an independent factor reducing three-year recurrence in acute ischemic stroke (HR = 0.594, 95% CI: 0.376-0.938). CONCLUSION: Treatment with fluoxetine for 90 days after acute ischemic stroke significantly reduces the three-year recurrence rate of ischemic stroke.

Dexmedetomidine pretreatment attenuates propofol­induced neurotoxicity in neuronal cultures from the rat hippocampus.

Propofol is widely used for the induction and maintenance of pediatric anesthesia. Previous studies have indicated that propofol can induce apoptosis, and damage cognitive and memory functions. Dexmedetomidine is a potent α­2 adrenoceptor agonist with high selectivity. Previous observations have shown that dexmedetomidine exhibits anti­apoptotic qualities. The present study evaluated the neuroprotective effects of dexmedetomidine pretreatment against propofol­induced neurotoxicity in immature hippocampal neurons. The viability and apoptotic rate of the neurons were detected using a Cell Counting Kit­8 assay and flow cytometry. The mRNA and protein expression levels of brain­derived neurotrophic factor (BDNF), B­cell lymphoma­2 (Bcl­2) and phosphorylated­cyclic­AMP response element binding protein (p­CREB) were detected using semiquantitative reverse transcription­polymerase chain reaction and western blot analyses, respectively. These results showed that propofol exposure (100 µM; 3 h) reduced neuronal viability, induced cell apoptosis and decreased the expression levels of BDNF, Bcl­2 and p­CREB. Dexmedetomidine treatment (0.001­100 µM) of the neurons prior to propofol exposure attenuated the propofol­induced neuronal apoptosis and increased expression levels of BDNF, Bcl­2 and p­CREB compared with the propofol only group. In addition, dexmedetomidine at the highest concentration provided superior neuroprotection of neurons. These in vitro data indicated that dexmedetomidine exerted direct neuroprotective effects to prevent cultured hippocampal neuronal injury caused by propofol, accompanied by an increase in the levels of p­CREB, Bcl­2 and BDNF.

Comparison of three ventilatory modes during one-lung ventilation in elderly patients.

OBJECTIVE: The purpose of this study was to explore the effects of three different ventilatory modes: volume controlled ventilation (VCV), pressure controlled ventilation (PCV) and pressure controlled ventilation-volume guaranteed (PCV-VG) on arterial oxygenation and airway pressure during one-lung ventilation (OLV) in elderly patients. METHODS: We enrolled 66 patients who underwent thoracic surgery requiring at least 1 hour of OLV and aged above 65 years into the study. Patients were classified into VCV, PCV and PCV-VG groups according to a controlled, randomized design. Patients were ventilated to obtain a tidal volume (TV) of 8 mL/kg with three different ventilatory modes during OLV. The Hemodynamic and respiratory data had been recorded during intraoperation and arterial blood gases were obtained at baseline, 20, 40, 60 minutes after OLV, end of surgery. RESULTS: Compared with VCV group, Ppeak was significantly lower in PCV and PCV-VG group (P<0.05), and the difference was not found between the PCV and PCV-VG group. PaO2 in PCV and PCV-VG group were higher than VCV group after the point of OLV+40 (P<0.05). Comparison of PCV group, PaO2 in PCV-VG group was higher, but did not show a significantly improved during OLV (P>0.05). CONCLUSIONS: Compared with VCV, the use of PCV and PCV-VG have a significant advantage in intraoperative oxygenation and airway pressure for eldly patients undergoing OLV.

Propofol inhibits proliferation and induces neuroapoptosis of hippocampal neurons in vitro via downregulation of NF-κB p65 and Bcl-2 and upregulation of caspase-3.

Propofol is widely used in paediatric anaesthesia and intensive care unit because of its essentially short-acting anaesthetic effect. Recent data have shown that propofol induced neurotoxicity in developing brain. However, the mechanisms are not extremely clear. To gain a better insight into the toxic effects of propofol on hippocampal neurons, we treated cells at the days in vitro 7 (DIV 7), which were prepared from Sprague-Dawley embryos at the 18th day of gestation, with propofol (0.1-1000 µM) for 3 h. A significant decrease in neuronal proliferation and a remarkable increase in neuroapoptosis were observed in DIV 7 hippocampal neurons as measured by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay and apoptosis assay respectively. Moreover, propofol treatment decreased the nuclear factor kappaB (NF-κB) p65 expression, which was accompanied by a reduction in B-cell lymphoma 2 (Bcl-2) mRNA and protein levels, increased caspase-3 mRNA and activation of caspase-3 protein. These results indicated that downregulation of NF-κB p65 and Bcl-2 were involved in the potential mechanisms of propofol-induced neurotoxicity. This likely led to the caspase-3 activation, triggered apoptosis and inhibited the neuronal growth and proliferation that we have observed in our in vitro systems.

Exogenous morphine inhibits human gastric cancer MGC- 803 cell growth by cell cycle arrest and apoptosis induction.

Morphine is not only an analgesic treating pain for patients with cancer but also a potential anticancer drug inhibiting tumor growth and proliferation. To gain better insight into the involvement of morphine in the biological characteristics of gastric cancer, we investigated effects on progression of gastric carcinoma cells and the expression of some apoptosis-related genes including caspase-9, caspase-3, survivin and NF-κB using the MGC-803 human gastric cancer cell line. The viability of cells was assessed by MTT assay, proliferation by colony formation assay, cell cycle progression and apoptosis by flow cytometry and ultrastructural alteration by transmission electron microscopy. The influences of morphine on caspase-9, caspase-3, survivin and NF-κB were evaluated by semi-quantitative RT-PCR and Western blot. Our data showed that morphine could significantly inhibit cell growth and proliferation and cause cell cycle arrest in the G2/M phase. MGC-803 cells which were incubated with morphine also had a higher apoptotic rate than control cells. Morphine also led to morphological changes of gastric cancer cells. The mechanism of morphine inhibiting gastric cancer progression in vitro might be associated with activation of caspase-9 and caspase-3 and inhibition of survivin and NF-κB.